LEP-2/Makorin regulates LIN-28 stability to promote the juvenile-to-adult transition in Caenorhabditis elegans

Abstract

The heterochronic genes lin-28, let-7, and lin-41, regulate fundamental developmental transitions in animals, e.g. stemness vs. differentiation and juvenile vs. adult states. We identify a new heterochronic gene, lep-2, in Caenorhabditis elegans. Mutations in lep-2 cause a delay in the juvenile/adult transition, with adult males retaining pointed, juvenile tail tips, and displaying defective sexual behaviors. In both sexes, lep-2 mutants fail to cease molting or produce an adult cuticle. We find that lep-2 post-translationally regulates LIN-28 by promoting LIN-28 protein degradation. lep-2 is the sole C. elegans ortholog of the Makorin (Mkrn) family of proteins. Like lin-28 and other heterochronic pathway members, vertebrate Mkrns are involved in developmental switches, including the timing of pubertal onset in humans. Based on shared roles, conservation, and the interaction between lep-2 and lin-28 shown here, we propose that Mkrns—together with other heterochronic genes—constitute an anciently conserved module regulating switches in development.